Genodermatoses are heritable in nature and arise from mutations in various genes essential for normal functioning of the skin and represent most challenging and intractable skin diseases with no clinically applicable therapies available. Dystrophic epidermolysis bullosa (DEB) is an inherited mechanobullous disorder characterized by fragility of the skin and mucous membranes. The morphological hallmark of DEB includes splitting of the basement membrane zone of the dermal-epidermal junction, with a cleavage plane lying within the papillary dermis. The abnormal assembly of anchoring fibrils is caused by genetic mutations in the gene (COL7A1) encoding collagen type VII synthesized by basal keratinocytes of the epithelium and the fibroblast of the papillary dermis. Precise understanding of the genetic lesions underlying different subtypes of DEB, and elucidation of the consequences of such mutations at the protein level, enabled us to continue our attempts to develop therapy approaches towards counteracting the clinical manifestations in this devastating skin disease. Recent advances in clinical stem cell research have raised the possibility that use of adult stem cells (ASC) may provide dramatic new therapy for treatment of DEB. This proposal is a logistical extension of our work in the field of stem cell-based therapy. Recently, we have shown that a transplantation of congenic ASC into skin of newborn mice affected with the recessive form of dystrophic epidermolysis bullosa (RDEB) leads to the production of the type VII collagen, localized restoration of the basement membrane zone, and correction of skin fragility, thus, supporting our original hypothesis on the feasibility of the therapeutic application of the ASC for the treatment of DEB. However, to make this approach broadly applicable for the treatment of genodermatoses, it is crucial to understand mechanisms that promote directional migration of ASC in the skin. The mechanisms underlying targeted-homing of ASC to cutaneous tissue remain to be elucidated, although our current studies suggest that both chemokines and their receptors and other adhesion molecules are involved. Studying their role on ASC may allow the development of therapeutic strategies to enhance the recruitment of ex vivo-cultured ASC to damaged or diseased tissues. This in turn could lead to various therapeutic possibilities such as supporting tissue regeneration, correcting inherited disorders, and using ASC as a vehicle for the delivery of biological agents. Overall, this grant application is aimed to identify factors that control directional migration of ASC into skin in normal and pathologic conditions. This proposal outlines a dedicated strategy of cell-based therapy aimed at the treatment of connective tissue disease in a clinically relevant model, epidermolysis bullosa, which provides an excellent genetic target for suggested therapy. A successful outcome of these studies may form a platform for development of a novel therapeutic approach for curing connective tissue disorders as well as other human genetic disorders.